of basel



Patented Oct. 23, 1928.

UNITED STATES PATE T oFIFICE;

KARL MIESCHER, OF B ASEL, SWITZERLAND, ASSIGNOR TO SOCIETY OF CHEMICAL INDUSTRY IN BASLE; OF BASEL, SWI'JPZIEIRILAND..

DERIVATIVES or QUINOLINE cannoxxmc Aoms AND rnoonss or MAKING s'Amn.

No Drawing. Application filed ilpril 19, 1927, Serial No. 155,067, and in Switzerland Apr-i130, 1926,

The present invention relates to new substituted derivatives of-quinoline carboxylic acids useful in therapeutics, and it comprises the new compounds themselves and the process of making same.

The new compounds are obtained by causing an acid halide of a'halogen quinoline carboxylic acid to react with a nitrogen compound of the general formula wherein R, and'R mean H, or any monovalent radical. The halogen quinoline carboxylic acid amides thus obtained are then caused to react with compounds of the formula RO H, B being any monovalent radical in presence of an agent binding hydrohali-cacid. There are thus formed 0-. substituted quinoline carboxylic' acidamides.

There are thus obtained, for example from a-chloro- -quinoline carboxylic acid chloride and diethylam'ine, the a-chloro-y-quinoline carboxylic acid diethylamide and treatment of this with sodium' alcoholate in alcoholic 7 solution or with alcoholic figtash produces the a-ethoxy-y-q'uinoline car xylic acid d1- ethylamide. 4

' C0-N(QIHI)I Instead of a-halog'en- -quinoline 'carboxylic acid halidesthere maybe used any other holagen quinoline carboxylic acid halide wherein the halogen is in the heterocyclic ring, for instance y-halogen-a-quinoline car-,

boxylic acid halide, The term halogen quinoline carboxylic acid includes any nu cleal substitution derivatives of these.

I 1. a-chloro-y-quinoline filtered and] washed with water.

The following examples illustrate'the invention, the parts being by weight v ExAMrLE I. ;-0-lzl0r0-gmnoline ccrbomylz'c acid amides.

carboxyllc acid dimethylamide of the rmua semen),

7 Then recrystallized from alcoholit forms colourless crystals of melting point 114 C.

, 2. ix-chloro y-quinoline carboxyllc acid diethylamide of the" formula r. I

J-ci N y-quinolinecarboxyli-c acid chloride is mixed gradually, while cooling, with 1.5 part of diethylamine. When the reaction is complete, 1

the separated'dieth lamine hydrochloride is filtered, washed wit benzene and the solvent a little alcohol to obtain the a-ChIOIO-y-qUlIIO- line carboxylic acid diethylamide which forms colourless crystals of melting point pounds can emade Melting I Point 1 I Properties.

1. a-chloro-y-qulnoline carboxylic aeid-dipropyl amide 77 0. columns crystals. 2. a-chloro-'y-quinoline oarboxyllc acld-diallylamido of the formula..- Do. 1

distilled. The residue is recrystallized from 7. a-chloroy-quinoline carboxylie acid-benzylamide Melting Properties.

point.

Yellowish oil, boiling point 185 under 0.015 mm. pressure.

4. d-chlOrWy-qlllllOliflG carboxylic acid-piper'idide 140 0. 00] less t i 5. q-ehloro- -quinoline carboxylic acid-N-ethylanilide of the formula 126 0. l crys 81s 01H: CO.N

N Cl

' 6. a chloro-y-quinoline carboxylic acid-monoethyl amide. 143 (3, Do. 217 C. DO.

EXAMPLE II. Alkomg gm'noline carbowylz'c acid amides.

1. a-ethoxy y-quinoline carbox ylic acid dimethylamide of the formula v CO.N(CH:)21

, soluble in most organic solvents, except cold petroleum ether. mineral acids.

Instead of sodium ethylate a solution of an alkali hydroxide in aqueous alcohol may be used for the reaction.

2. a-cyclohexyloxyquinollne earboryllo acid diethylainide of 1 the formula GO. N(C:Hs) a CHI-011x 0. Cl! C 2 CHz-CH A mixture of 12 parts of cyclohexa-nol, 7 0 arts of xylene and 2.5 parts of sod um is oiled until all the sodium has disappeared.

It is also easily soluble in 'Afteraddition of 26 parts 'of a-Cl'llOIO-y-(llllflolinecarboxylic acid diethylamide boiling is continued and after the reaction is complete the mixture is extracted with water and the solventdistilled. a-cyclohexyloxy- -quinoline carboxylic acid diethylamide remains as a nearly colourless oil which gradually solidifies. When recrystallized from petroleum ether it melts at 63 C. It is easily soluble in organlc solvents, except cold petroleum ether.

3. aioplhlalllfiigy -quinoline carboxyllc acid diethylamide of the I CO.N(C:H;): I

amide o! the formula CO- N(C:H:):

12 parts of diethylamino ethanol are made to react with 2.3 parts of sodium in benzene solution. When the sodium is dissolved, 26- parts of a-chloro- -quinoline carboxylic acid diethylamide are added, whereu on reaction occurs with ebullition and tur idity. The

whole is boiled for a long time and when it has been cooled the base is extracted by means of acid and separated. Sodium carbonate precipitates the base'and it may be isolated y extraction with other. There is thus obtained the a-diethylamino-ethoxy- -quinoline carboxylic acid diethyl amide in t e form of a yellowish oil which dissolves easily in all organic solvents and in acids. It boils at 168-17 0 C. under 0.005 mm. pressure.

a. qz-ethoxy-v-quinoline carbo xylic acid amide or the formula coma 10 I A mixture of 1 part of a-chloro- -quinoline carboxylic acid amide (seeMulert, Berl. Ber.

39, 1906, page 1903) with a solution of 0.2 part of sodium in alcohol is boiled until reaction is complete. The mixture is then diluted with water and filtered from the separated a-ethoxy- -quinoline carboxylic acid amide.

3g Properties.

1. According to Example 11 (1):

a-methoxy-y-quinoline carboxylic acid-diethylamide.-- 93 C. Colourless crystals. a-ethoxy- -quinoline carboxylic acid-diethylamideh 68 C. D0. a-propyloxy-y-quinoline carboxylic acid-diothylamidn 61 0. D0. a-isopropyloxyy-quinolinecarboxylic acid-diethylamide- Colourless oil. a-allyloxy-y-quinoline carboxylic acid-diethylamide 33 C. Colourless crystals. methoxy- -quinoline carboxylie acid-dipropylamide 0. Do. a-ethoxy-y-quinoline carboxylic acid-diallylamide- 53 0. Do. a-ethoxy-v-quinoline 'carboxylic acid-di-isoamylamide. Yellowish oil. a-ethoxy-y-quinoline carboxylic acid-piperi i e 90 C. Colourless crystals. a-ethoxyquindline carboxylie acid-N-ethylanili a Yellowlsh oil.

2. According to Example II (2): I

a-phenethoxy-y-qulnoline carboxylic acid diethylamide of the formula 59 C colourless crystals.

3. According to Example II (4):

a-diethylamino-ethoxy y-qulnoline carboxylic acid anillde 122 0 Do.

4. According to Example Ii 5 e Hthoxy- -quinoline carhoxylic acid monoethylamldeu" 152 0. Do. a-ethoxy-y-quinoline carboxylic acid benzylamidn 166 0 Do.

What I claim is 1. A process for the manufacture of substituted derivatives of quinoline carboxylic acids by causing an acid halide of a halogen quinoline carboxylic acid wherein the halogen is in the heterocyclic ring to react with a nitrov gen compound of the formula H-N BI, wherein Rpand R mean H, or any monovalent radical. 2. A process for the manufacture of substituted derivatives of quinoline carboxylic acids by causing an acid halide of an a-halo gen quinoline-carboxylic acid to react with a gen- -quinoline carboxylic acid to react with a nitrogen compound of the formula wherein R, and R mean H, or any monovalent radical. v 4. A process for the manufacture of substituted derivatives of quinoline carboxylic acids by causing an acid halide of a halogen quinoline carboxylic acid wherein the halo en is in the heterocyclic ring to react wi a nitrogencompound of the formula R: wherein R, and R mean H, or anymonovalent radical, and causing the halo en quinoline carboxylic acid amides thus o tained to reactwith compounds of the formula ROH, B being any monovalent radical, in presence of an agent binding hydrohalic acid.

5. A process for the manufacture-0f substituted derivatives of quinoline carboxylicacids by causing an acid halide of an a-halogen quinoline carboxylic acid to react with a nitrogen compound of the formula RI I wherein R and R meanH, or any monoir-N 'valent radical, and causing the a-halogen quinoline carboxylic acid amides thus. obtained to react with compounds of the formula ROH, R being any monovalent radical, in

presence of an agent binding hydrohalic acid.

6. A process for the manufacture of substituted derivatives of quinoline carboxylic acids by causing an acid halide of, an a-halogen- -quinoline carboxylic acid to react with a nitrogen compound of the'formula substituted derivative ofquinoline carboxylic acid by causing an acid halide of u-chloro- -quinoline carboxylic acid to react with dimethylamine and ca-usin'gthe on chloro -quinoline carboxylic acid dimethylamide thus obtained to react with ethyl alcohol in presence of an agent binding hydrohalic acid.

a 8. As new products derivatives of halogen quinoline carbo lic acid' amides wherein the halogen is' in the eterocyclic ring, and is substituted by a gran OR, B being any monovalent radical, sai products being useful in thera eutics. a v

9. s new products derivatives of a-halo gen quinoline carboxylicacid amides wherein the halogen is substituted by a group'OR, R

'being any monovalent radical, said products being useful in therapeutics. I

10. As new products derivatives of a-halogen -quinoline carbo lic acid: amides wherein the halogen is su tituted by a group OR, R'being'a'ny monovalentradical, said products being useful in therapeutics.

11; As a new product the a-ethoxyuinoline carboxylic acid dimethylamide o the formula co. morn),

which forms colorless crystals of melting point 69 and is easily soluble in most organic solvents except in cold petroleum ether and likewisesoluble in an-excess of aqueous mineral acids, said product being useful in therapeutics. v

In witness whereof I have hereunto signed my name this 7th day of April 1927. v p

' KARL MIESOHER. 

